Doctors have always provided treatments that did not have a track record in randomized, controlled trials. Often they've provided such treatments without any serious intent of obtaining scientific validation.

Rather, they were usually convinced that the treatments would work, or at least that their errors would eventually lead them to discover a real therapy.

It has also been the case that these doctors have been treated with disdain, even persecuted by the medical establishment.

Many of them retreated to the shadows, continuing to practice their brand of medicine but with a low profile. Others proudly soldiered on in what they believed to be a noble, though lonely, cause.

Now, however, they organize.

Case in Point: 'Chronic Lyme disease'

The "Lyme Wars" have raged almost since the disease was first described in 1977 as a cluster of unexplained cases of arthritis among children in Lyme, a small town in Connecticut.

On one side are infectious disease experts, who have determined that Lyme disease is a straightforward infectious disease, caused by a specific spirochete and characterized by a defined constellation of symptoms ranging from a rash and arthritis to neurologic and cardiac manifestations.

Treatment, according to those on this side of the argument, is based on a limited (usually less than 30 days) course of antibiotics.

On the other side are a group of physicians and patients who believe that Lyme disease can persist for years, even decades, causing pain, fatigue, and other symptoms -- even in the absence of hard evidence that they were ever infected with the Lyme parasite.

The patients are eager for treatments to relieve their misery, and the physicians are willing to provide it, often taking the form of antibiotic regimens that last for months.

But this latter group has failed to gain acceptance from mainstream medical authorities such as the Infectious Diseases Society of America (IDSA).

Guidelines Also at War

In 2000, the IDSA published guidelines on the diagnosis and treatment of Lyme disease, sparking a controversy that has no end in sight.

Those guidelines have resulted in legal and professional actions against some clinicians who used treatment approaches outside the guidelines and particularly lengthy courses of antibiotics. Insurance companies have refused to reimburse patients for such treatment.

In those guidelines, IDSA stated that there was no convincing evidence for the existence of chronic symptomatic B. burgdorferi infection, and that the risks of long-term antibiotic therapy do not outweigh the benefits.

A group of physicians who believe Lyme is more than an infection -- the International Lyme and Associated Diseases Society (ILADS) -- responded by convening a panel of its own, and in 2004 published their guidelines, criticizing IDSA.

"Guidelines of the Infectious Diseases Society of America fall short of meeting the needs for diagnosis and treatment of individuals with chronic Lyme disease. The latest IDSA guidelines fail to take into account the compelling, peer-reviewed, published evidence confirming persistent, recurrent, and refractory Lyme disease and, in fact, deny its existence," ILADS statement read.

IDSA subsequently agreed to review the scientific evidence available and formulate new guidelines, which were published in October 2006.

These updated recommendations reiterated the group's original position: A diagnosis of Lyme disease requires laboratory confirmation of infection, and there is no convincing evidence for symptomatic chronic disease among patients treated with appropriate antibiotic regimens.

"Only high-quality, prospective, controlled clinical trial data demonstrating both benefit and safety will be sufficient to change the current recommendations," the revised guidelines stated.

In Connecticut -- ground zero of Lyme disease -- advocacy groups led by the California Lyme Disease Association went to work. They ultimately convinced the Connecticut attorney general, Richard Blumenthal, to launch an antitrust investigation against IDSA, citing conflicts of interest among the society's guidelines panel, inadequate quality of evidence, and a lack of preservation of the principles of patient autonomy and choice.

After an 18-month investigation by Blumenthal's office, IDSA agreed to convene a new panel, free of potential conflicts, that would be more representative of differing viewpoints.

In April of this year, the new panel issued a final statement, again almost unanimously supporting the society's original recommendations.

"It's a sad day for the healthcare system and for everyone who suffers from the Lyme disease epidemic," said Robert C. Bransfield, MD, a psychiatrist in Red Bank, N.J., and president of ILADS.

'Chronic Lyme' Gets Organized

ILADS was formed in 1999 as a group of physicians with the stated mission of advancing the science, clinical understanding, and management of tick-borne diseases.

Central to the group's philosophy is a belief that Lyme disease is more than an infection by Borrelia burgdorferi.

"We are the physicians who treat these patients day after day, year after year, sometimes for decades, and have the long-term responsibility for them," Bransfield said.

One of the other founders of ILADS, Bernard Raxlan, MD, has a full-time practice devoted to caring for Lyme disease patients. Of the organization, he said, "I've watched it grow and seen its influence in the academic world as well, making the whole field much more readily available to the lay public."

The group has also engaged in the policy arena, working to advance legislation requiring insurance coverage for extended chronic-Lyme treatment regimens.

State legislatures in Connecticut and Massachusetts have passed laws protecting physicians who prescribe long-term antibiotics for their patients.

Chapter 112 of the Massachusetts General Laws now states: "A licensed physician may prescribe, administer or dispense long-term antibiotic therapy for a therapeutic purpose to eliminate infection or to control a patient's symptoms consistent with a clinical diagnosis of Lyme disease, if such clinical diagnosis and treatment are documented in the patient's medical record by the prescribing licensed physician."

ILADS was also a vocal supporter of Blumenthal's attempted takedown of the IDSA guideline.

Other Voices Enter the Fray

Another group that voiced objection to the IDSA recommendations was the Association of American Physicians and Surgeons (AAPS). This group was founded in 1943 with the goal of fostering private, physician-patient centered medicine.

"These guidelines should be revised to recognize that the physician must retain full flexibility in the diagnosis and treatment of Lyme disease. Medical societies do not practice medicine; physicians do," reads a statement by this group.

AAPS goes much further in its advocacy for patient choice. Of the American Medical Association, AAPS spokesperson Jane Orient, MD, said, "AMA is very much into corporate medicine and government-dictated guidelines, which they hope to be engaged in writing -- for profit. They believe they can formulate best practices for everybody."

This creates risks for patients and physicians alike, when clinicians fear that they are being watched and could lose their licenses and worse, according to Orient.

"Those doctors have been viciously attacked, even by their own medical boards and by the societies that consider themselves the only source of expertise. Insurance companies are behind this because they don't want to pay for the treatment. Long-term antibiotics can be very expensive," she told MedPage Today.

Gary P. Wormser, MD, an infectious disease expert from New York Medical College in Valhalla, and the lead author of the original IDSA guidelines, disagrees with the long-term use of antibiotics but acknowledges frustration with the medical community.

"There are a lot of people out there with medically unexplained symptoms who are eager to find help. I don't blame them, and we have to admit that to some extent the mainstream medical community hasn't been very helpful for their chronic fatigue, joint pains, and other problems," he said.

It must be appealing for these patients when, after months or years of poor health a physician finally says, "I know what you have and I know how to treat it," Wormser said.

"If I were in their shoes I might find that appealing as well," he added.

But randomized NIH-sponsored trials of patients who have had documented Borrelia infections and had persistent subjective symptoms have found no benefit to additional antibiotic treatment.

"One thing we learned from the antibiotic trials was that 36% of patients who received placebo got better, which was really remarkable," Wormser said.

So why not let patients have the antibiotic treatments they believe can help them?

"Because antibiotics aren't really all that safe when you take them long term and unnecessarily," he said, citing risks of intravenous lines, sepsis, and potentially lethal infections.

On the individual level antibiotics also can interfere with the normal bacterial flora, and on the societal level the concern is the creation of more resistant bugs.

"I don't know what the remedy is," Wormser said. "If someone would come up with genuine help for these patients, they wouldn't have to turn to alternative practitioners."

Autism: Desperate Parents, Docs With Answers

Like the patients with mysterious pains and fatigue with no textbook-validated explanation or treatment, parents of children with autism are also desperate for answers.

Recent reports indicate a rising prevalence of autism spectrum disorders, now standing at about one in every 100 children.

Complicating the issue is the elusive cause of autism, although both genetics and environment are thought to play a role.

The foundation of treatment remains behavioral and educational interventions with support from medications -- such as the antipsychotics risperidone (Risperdal) and aripiprazole (Abilify) -- to ease some of the behavioral problems common in children with autism.

The treatment with the best evidence of efficacy is applied behavior analysis (ABA), although the data even for that are not strong, acknowledged Susan Hyman, MD, a pediatrician at the University of Rochester and chair of the American Academy of Pediatrics' autism subcommittee.

Into this void of scientifically proven treatments have stepped providers of so-called biomedical treatments of autism -- also called complementary, alternative, or integrative practices.

These treatments include restrictive diets such as the popular gluten/casein-free diet, vitamin supplementation, treatments to heal the gut, hyperbaric oxygen therapy, chelation therapy, and many more regimens designed to address the biological symptoms of autism.

Although there is little evidence that these highly popular treatments work, Hyman said that families seek them out because of a hope that something that has not yet been proven by science will help their child.

Finding Strength in Numbers

Organizations have formed to promote these treatments, perhaps most notably the Autism Research Institute (ARI) and its Defeat Autism Now! (DAN!) program.

"Our approach is to learn from one another about medical problems associated with autism," according to Stephen M. Edelson, PhD, director of the ARI.

"We advocate conducting the necessary lab tests and seeking opinions from experts to figure out the best treatments," he wrote in an e-mail to MedPage Today. "At the same time, we are informing researchers about these clinical experiences through our think tanks, conferences, and discussion groups, and we encourage them to conduct the indicated needful research."

But evidence supporting the effectiveness of the integrative treatments of autism is lacking.

Edelson suggested that previous studies have failed to show a benefit because there may be as many as 25 different types of autism.

"No one would expect that any one treatment will be equally effective for each subtype," he said, adding that it is difficult to get funding for studies of nondrug therapies.

James Neubrander, MD, a physician based in Edison, N.J., who ascribes to the DAN! approach, told MedPage Today that studies of the integrative therapies for autism have failed because autism is not a condition conducive to study using traditional randomized controlled trial methods.

Studies trying to assess an autistic child's progress at set time points will inevitably fail because autistic children will not speak or perform a task on demand, he said.

"With a family with autism, what they know is that you cannot 'mand,'" Neubrander said. "'Manding' is commanding a kid to do something or demanding them to do something."

"I'm not putting [that method] down," Neubrander said. "I believe in it. But ... there has to be another way of looking at it."

A better way to assess progress for a child with autism would be to involve all people in a child's life -- the parents, bus driver, pediatrician, teachers, and others. All of these sources would be able to record instances when the child performed a task or said something they hadn't before, Neubrander said.

In that way, anecdotal evidence would be systematically recorded, he said.

Where's the Beef?

But, Hyman countered, "I believe that using anecdotal data and clinical experience, while important in the art of medicine, is really used to inform the studies that need to be done."

She disputed the assertion that autism was not amenable to study using traditional scientific methods, noting that some of the most complete data for an autism treatment exist for secretin, an integrative therapy that has not been shown to be effective.

"It is possible to study an intervention in autism," she said, "and I would argue that all interventions require effectiveness and/or efficacy studies, including conventional interventions."

"We need to know what it is we're doing so that we can use our scarce resources in the most effective way."

According to Hyman, there is an impasse between individuals who want to make decisions on the basis of what they see as progress and those pushing for evidence-based practice.

She acknowledged that that impasse is unlikely to be overcome with more research because of the philosophical differences.

But, says Hyman, "there's no substitute for the hard work of science. That's what families need to make good decisions."

Families also need to understand that organizations like DAN! and others promoting integrative practices operate without oversight from a boarding agency, she said.

Such groups of physicians create "a platform for dissemination of the beliefs and the ideas," Hyman said. "Because many of these are nonstandard practices, it provides a club to legitimize practice within a community."

While providing a group in which to share ideas, support colleagues, and conduct research, such alliances are also a way of attracting referrals, although that is no different than for physician groups recognized by boarding agencies, Hyman said.

"It's like the Good Housekeeping seal of approval showing someone has reached a certain level of competence as recognized by a national body," she said.

To this end, DAN! is in the process of developing a certification process, according to Neubrander, to provide patients with a resource to find legitimate practitioners of the integrative autism therapies.

Hyman pointed out that, even though the integrative treatments have not been shown to be effective in clinical trials, it does not mean that they never will be.

She noted that ABA, which serves as a cornerstone of conventional autism treatment, was practiced by a group of "renegades" not too long ago but is now the legally mandated treatment in some states.

"Things that may start out as being novel and unproven may be proven with further research," she said.

There is an understanding coming from both sides of the issue that physicians, in general, have the best interests of the children in mind.

"Everybody is really trying. I don't fault anybody for trying," said Neubrander, who maintained that mainstream autism researchers are handcuffed by the traditional randomized controlled trial method.

Hyman also did not fault the intentions of physicians on the integrative side.

"I think that it is untrue if complementary groups say that traditional physicians are not interested and at the same time I think it's untrue if traditional physicians say that complementary practitioners are only businessman," Hyman said. "You don't get into this field without truly wanting to help the children."

The Stem Cell Debate Reaches the Clinic

It would not be surprising if patients with incurable degenerative diseases would take notice of doctors who offer nonsurgical treatments with the potential, if not an outright promise, to halt or even reverse the disease process.

Add the magic words "stem cells" and patients will probably pay more attention, given two decades of hype in the popular media and, for research on human embryonic stem cells, its role as a political football.

Although the field remains in its infancy, according to academic researchers working in it, that hasn't stopped dozens of physicians, clinics, and companies from offering therapies based on stem cells to patients willing to pay.

Recently the FDA cracked down on one such provider, Colorado-based Regenerative Sciences, which offers a treatment for knee osteoarthritis, degenerated spinal disks, and other joint diseases, based on autologous mesenchymal stem cells in bone marrow.

The agency said the treatment requires FDA approval, which the firm had not sought, because the autologous cells undergo extensive ex vivo manipulation and are used for a "nonhomologous" purpose that is a function the cells do not normally perform in the body.

Numerous other firms offer similar therapies, often in foreign countries where they are beyond the FDA's reach. Although they sometimes publish in the conventional literature -- the Regenerative Sciences physicians published safety data in Current Stem Cell Therapy and Research on 227 patients they have treated -- randomized, controlled trials are virtually nonexistent.

It's probably also no surprise that the medical establishment takes a dim view of these therapies.

Elaine Fuchs, PhD, of Rockefeller University, and president of the International Society for Stem Cell Research (ISSCR) -- a group for academics who conduct basic research on stem cells -- told MedPage Today that only three forms of stem cell therapies had been tested sufficiently to warrant use in patients outside a clinical trial setting.

These include autologous and allogeneic hematopoietic stem cell transplants for patients undergoing marrow ablation, and stem cell-based skin and corneal grafts for patients with severe burns.

Otherwise, Fuchs said, physicians should only use stem cell therapies on patients in a formal clinical trial -- and with oversight from government regulators.

She declined to comment on specific treatments, but said, "We do have concerns that some stem cell treatments are being marketed to patients around the world. ... the ISSCR feels strongly that clinical trials are the best way."

Her predecessor as ISSCR president, Irving Weissman, MD, of Stanford University, was less diplomatic last year when approached by CNN for a story about a stem cell therapy for heart failure and COPD.

It's offered by a company called Regenocyte, headed by Zannos Grekos, MD, in Bonita Springs, Fla., although the actual treatments are delivered in the Dominican Republic at a reported cost of more than $50,000.

"As a stem cell scientist who works in the field of regenerative stem cells, I am disappointed and shocked that somebody would prey on a family that has an untreatable disease with the promise of a therapy that has no scientific or medical basis," Weissman told CNN.

Seeking Validation

The stem cell therapists, too, have formed their own group: the International Cellular Medicine Society (ICMS).

The ICMS shuns the confrontational attitude of the "chronic Lyme" physician groups, preferring the low-key approach of ARI and DAN! in the autism community.

David Audley, executive director of the ICMS, told MedPage Today that the organization's current mission is to develop best-practice guidelines and maintain registries of patient outcomes and complications.

"We do no lobbying or advocacy," he said. "We may at some point get into an advocacy role, but I don't see that happening until we're a lot larger organization."

For one thing, he noted, the ICMS is genuinely an international group. Most of its members are either based outside the U.S. or send patients abroad to receive treatments.

Lobbying the FDA "puts too much focus on the U.S.," Audley said, adding that his meetings with regulatory officials largely involved those from other countries.

The main issue, he explained, is that cell-based therapies are often not addressed in national regulations. "We're hoping for a clearing of the regulatory fog," he said.

Audley told MedPage Today that the group believes in a light regulatory hand, given that practically all the therapies now on offer are autologous treatments that theoretically should pose little danger to patients.

He likened the field to the early days of open-heart surgery and organ transplantation, which also were led by individual, independent clinicians working largely without regulation.

He said oversight of stem cell pathways should take a "similar pathway."

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